Biology subjects

Decker, L.

Publications and source records attributed to Decker, L..

5 recordsLinked to original sources

bioRxiv2025

Loss of FXR1 and FXR2 promotes accumulation of TDP-43 in aging-related stress granules

Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 in vulnerable neurons may accompany the primary neuropathology of various neurodegenerative diseases, or represent the hallmark of others, such as amyotrophic lateral sclerosis. Aging is the major risk factor for neurodegeneration, and sufficient to induce accumulation of TDP-43 in chronic cytoplasmic stress granules possibly further maturing to irreversible aggregates. Reduced expression of Fragile X protein (FXP) family members (FMR1, FXR1 and FXR2) in vulnerable neurons is associated with neurodegeneration, and loss of each individual FXP induces overlapping and unique aging-related phenotypes in HAP1 and SH-SY5Y cell models. Therefore, we analyzed consequences of FXP loss on TDP-43 cytoplasmic mislocalization and stress granule formation in fibroblast-like HAP1 FXP knockout cells. FXP loss induced nuclear pore pathology, and passive egress of proteins and RNA was evident upon loss of FXR1 or FXR2. Cytoplasmic mislocalization of TDP-43 was restricted to FXR1 knockout cells upon impairment of nuclear import, and cytoplasmic TDP-43 induced spontaneous stress granules exclusively in FXR2 knockout cells. In contrast, loss of FMR1 had no effect on nucleocytoplasmic exchange or TDP-43. Hence, reduced expression of FXR1 and FXR2 in aging and neurodegeneration may contribute to TDP-43 pathology.

cell biology↗

bioRxiv2025

Somatic mutations in ALS genes in the motor cortex of sporadic ALS patients

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of cortical and spinal motor neurons. Mendelian germline mutations often cause familial ALS (fALS) but only approximately ten percent of sporadic ALS cases (sALS). We leveraged DNA and single cell RNA-sequencing data from autopsy tissue to explore the presence of somatic mosaic variants in sALS cases. Deep targeted panel sequencing of known ALS disease genes in motor cortex tissue revealed an enrichment of low allele frequency variants in sALS, but not in fALS with an identified monogenic cause. In silico analysis predicted increased pathogenicity of mosaic mutations in various known ALS mutational hot spots. In particular, we identified the somatic FUS variant p.E516X, located in an established hot spot for germline ALS mutations, which leads to nucleo-cytoplasmic mislocalization and aggregation typical for ALS FUS pathology. Additionally, we performed somatic variant calling on single cell RNA-sequencing data from sALS tissue and revealed a specific accumulation of somatic variants in excitatory neurons, reinforcing a neuron-autonomous disease initiation. Collectively, this study indicates that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to sALS development.

genetics↗

bioRxiv2024

PIEZO-dependent mechano-sensing of the niche is essential for intestinal stem cell fate decision and maintenance

Stem cells continuously perceive and respond to various environmental signals to maintain homeostasis. In addition to biochemical factors, the stem cell niche is subjected to mechanical and physical cues. However, it remains unclear how stem cells can sense mechanical signals from their niche in vivo. Since intestinal stem cells constantly and directly face the external environment, we investigated the roles of mechano-sensing PIEZO ion channels in the gut stem cell niche. By employing mouse genetics and performing single-cell RNAseq analysis, we revealed the absolute requirement for PIEZO channels in intestinal stem cell (ISC) state dynamics and maintenance. In vivo measurement of basement membrane region stiffness demonstrated that ISCs reside in a more rigid microenvironment at the bottom of the crypt. Using 3D and 2D organoid systems combined with bioengineered substrates and a cell stretching device, we found that PIEZO channels are activated by high extracellular matrix stiffness and tissue tension to modulate ISC behavior. This study delineates the mechanistic cascade of PIEZO channel activation in ISCs from the upstream extracellular stimuli through the downstream signaling activation that coordinates stem cell fate decision and maintenance.

cell biology↗

bioRxiv2024

Vascular FLRT2 regulates venous-mediated angiogenic expansion and CNS barriergenesis

Veins have emerged as the origin of all other endothelial cell subtypes needed to expand vascular networks during developmental and pathological neoangiogenesis. Here, we uncover the significant role of the angioneurin Fibronectin Leucine Rich Transmembrane protein (FLRT) 2 in central nervous system (CNS) vascular development in the mouse. Early postnatal FLRT2 deletion reveals specific defects in retinal veins, impacting endothelial cell proliferation, sprouting and polarity that result in reduced tip cells at the vascular front. FLRT2 interacts with VE-cadherin and together with the endocytic adaptor protein Numb contribute to the modulation of adherens junction morphology in both retina and cerebral cortex in vivo. Utilizing expansion microscopy, we visualize the altered dynamic distribution of VE-cadherin in tissue of FLRT2 endothelial mutants. Additionally, FLRT2 in cortical vessels regulates the crosstalk between adherens and tight junctions, influencing blood-brain barrier development. Our findings position FLRT2 as a vein-specific crucial regulator of CNS vascular development.

neuroscience↗

bioRxiv2020

Higher Variability in Fungi Compared to Bacteria in the Foraging Honey Bee

Microbial communities in the honey bee gut have emerged as a model system to understand the effects of host-associated microbes on animals and plants. The specific distribution patterns of bacterial associates among honey bee gut regions remains a key finding within the field. The mid- and hindgut of foraging bees house a deterministic set of core species that affect host health. In contrast, the crop, or honey stomach, contains a more diverse set of bacteria that is highly variable in composition among individual bees. Whether this contrast between the two gut regions also applies to fungi, another major group of gut-associated microbes, remains unclear despite their potential influence on host health. In honey bees caught foraging at four sites across the San Francisco Peninsula, we found that fungi were much less distinct in species composition between the crop and the mid- and hindgut than bacteria. Unlike bacteria, fungi were highly variable in composition throughout the gut, and much of this variation was attributable to bee collection site. These patterns suggest that the fungi may be passengers rather than functionally significant gut symbionts. However, many of the fungi we found in the bees have been recognized as plant pathogens. Assuming that some fungi remain viable after passage through the gut, the distribution patterns we report here point to the potential importance of honey bees as vectors of fungal pathogens and suggest a more prominent role of honey bees in plant pathogen transmission than generally thought. Importance (Nontechnical explanation of why the work was undertaken)Along with bacteria, fungi make up a significant portion of animal- and plant-associated microbial communities. However, we have only begun to describe these fungi, much less examine their effects on most animals and plants. The honey bee, Apis mellifera, has emerged as a model system for studying host-associated microbes. Honey bees contain well-characterized bacteria specialized to inhabit different regions of the gut. Fungi also exist in the honey bee gut, but their composition and function remain largely undescribed. Here we show that, unlike bacteria, fungi vary substantially in species composition throughout the honey bee gut, contingent on where the bees are sampled. This observation suggests that fungi may be transient passengers and therefore unimportant as gut symbionts. However, our findings also indicate that honey bees could be major vectors of infectious plant diseases as many of the fungi we found in the honey bee gut are recognized as plant pathogens.

ecology↗